Chemosensory Systems: Sympathetic Modulation of Vomeronasal Neurons and Electrophysiological Insights from the Human Olfactory Epithelium

Olfaction enables the discrimination of millions of molecules across varied concentrations, with species adapting their olfactory systems to suit their ecological needs. Despite this variability, many mammals share a common olfactory anatomy involving the main olfactory epithelium (MOE) for detecting odorants and the vomeronasal organ (VNO) for sensing semiochemicals and pheromones. These functions are critical for identifying food sources, finding mates, and avoiding environmental dangers. In the first part of this thesis, we explored the VNO, an organ housing vomeronasal sensory neurons (VSNs) located in a secluded sensory epithelium, accessible solely through a duct in the nasal cavity. The entry of mucus laden with pheromones into this organ is facilitated by muscle contractions orchestrated by the sympathetic nervous system. This system governs fight-or-flight responses through the secretion of noradrenaline (NA) from sympathetic nerves or adrenaline from the adrenal gland, both capable of activating adrenergic receptors (AR). Our investigation focused on understanding how VSNs are modulated under sympathetic influence. Specifically, we examined NA's impact on the spiking activity of VSNs, which are crucial for detecting pheromones and other semiochemicals. Employing several techniques including patch-clamp whole-cell recordings, transcriptomic analysis, calcium imaging, and pharmacology, we identified alpha 1-AR as pivotal in mediating NA-induced increases in VSN firing frequency. Immunohistochemistry further revealed catecholaminergic fibers in the vomeronasal sensory epithelium, indicating localized NA release. These findings underscore NA’s critical role in VSNs and shed light on the intricate interplay between the sympathetic nervous system and chemosensory processing. In the second part of this thesis, we delve into the MOE, the tissue harboring olfactory sensory neurons (OSNs), responsible for the detection of odorant molecules. These bipolar neurons have dendrites ending with several cilia that contain the essential components for olfactory transduction. Studies on several vertebrates have shown that, upon binding of odorant molecules to specific odorant receptors (ORs), a transduction cascade is initiated, converting the chemical signal into an electrical one, which is then transmitted and processed by the central nervous system. This cascade involves the activation of adenylyl cyclase III (ACIII), which generates cAMP, subsequently activating cyclic nucleotide gated (CNG) channels. These channels permit the entry of both Na+ and Ca2+ ions into the cilia. The rise in Ca2+ levels then triggers the opening of the Clchannel TMEM16B, amplifying the primary CNG current response However, in the human MOE, there is a lack of information at the cellular physiology level, highlighting the necessity of developing a novel model to study it. Given the heightened focus on the MOE during the COVID-19 pandemic, we examined the cellular physiology of the MOE in humans, in acute slices of the human MOE from nasal biopsies. By using whole-cell patch-clamp techniques, we recorded voltage-gated currents in human OSNs and supporting cells (SCs). In OSNs, we recorded action potentials in response to current injections. Additionally, we found functional indications of a transduction cascade involving cAMP as a second messenger. Indeed, phosphodiesterase inhibitors and odorant mixtures triggered the activation of inward currents and action potential firing. This marks the first electrophysiological characterization of human OSNs, providing a foundation for future investigations into human olfactory physiology. Together, these results advance our comprehension of chemical sensory modulation in both the OSNs and VSNs, emphasizing NA’s significant regulatory role in VSNs and expanding the knowledge of olfactory mechanisms in human OSNs